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Background Tissue-resident memory T (Trm) cells are associated with cytotoxicity not only in viral infection and autoimmune disease pathologies but also in many cancers. Tumour-infiltrating CD103+ Trm cells predominantly comprise CD8 T cells that express cytotoxic activation and immune checkpoint molecules called exhausted markers. This study aimed to investigate the role of Trm in colorectal cancer (CRC) and characterise the cancer-specific Trm. Methods Immunochemical staining with anti-CD8 and anti-CD103 antibodies for resected CRC tissues was used to identify the tumour-infiltrating Trm cells. The Kaplan–Meier estimator was used to evaluate the prognostic significance. Cells immune to CRC were targeted for single-cell RNA-seq analysis to characterise cancer-specific Trm cells in CRC. Results The number of CD103+/CD8+ tumour-infiltrating lymphocytes (TILs) was a favourable prognostic and predictive factor of the overall survival and recurrence-free survival in patients with CRC. Single-cell RNA-seq analysis of 17,257 CRC-infiltrating immune cells revealed a more increased zinc finger protein 683 (ZNF683) expression in cancer Trm cells than in noncancer Trm cells and in high-infiltrating Trm cells than low-infiltrating Trm in cancer, with an upregulated T-cell receptor (TCR)- and interferon-γ (IFN-γ) signalling-related gene expression in ZNF683+ Trm cells. Conclusions The number of CD103+/CD8+ TILs is a prognostic predictive factor in CRC. In addition, we identified the ZNF683 expression as one of the candidate markers of cancer-specific Trm cells. IFN-γ and TCR signalling and ZNF683 expression are involved in Trm cell activation in tumours and are promising targets for cancer immunity regulation.

Background The efficacy of neoadjuvant chemotherapy (NACT) correlates with patient survival in oesophageal squamous cell carcinoma (OSCC), but optimal evaluation of the treatment response based on PET-CT parameters has not been established. Methods We analysed 226 OSCC patients who underwent PET-CT before and after NACT followed by surgery. We assessed SUVmax, metabolic tumour volume (MTV), and total lesion glycolysis (TLG) for the primary tumour and the number of PET-positive lymph nodes before and after NACT to predict patient survival. Results In a stepwise analysis, we defined 60%, 80%, and 80% as the optimal cut-off values for SUVmax, MTV, and TLG reduction, respectively, to distinguish responders and non-responders to NACT. In the ROC analysis, the TLG reduction rate was the best predictor of recurrence among PET-CT parameters. The TLG responders achieved significantly more favourable prognoses than non-responders (2-year progression-free survival [PFS] rate: 64.1% vs. 38.5%; P = 0.0001). TLG reduction rate (HR 2.58; 95% CI 1.16–5.73) and the number of PET-positive lymph nodes after NACT (HR 1.79; 95% CI 1.04–3.08) were significant independent prognostic factors. Conclusions TLG reduction is the best predictor of prognosis. Preoperative PET-CT evaluation of both the primary tumour and lymph nodes could accurately stratify risk in OSCC patients.

The thoracic duct (TD) plays an important role in nutrition and immunity but is often resected with the esophagus when dissecting surrounding lymph nodes in patients with esophageal squamous cell carcinoma (ESCC). We examined whether indiscriminate TD resection improved the prognosis of patients with ESCC treated with neoadjuvant chemoradiotherapy (NACRT) followed by esophagectomy.A total of 440 patients treated with NACRT followed by esophagectomy between 2007 and 2012 were analyzed using data from the Comprehensive Registry of Esophageal Cancer in Japan. The propensity score-matched TD resection and TD preservation groups were compared in terms of short- and long-term outcomes.After matching, there were 85 patients in both groups. No significant differences were found between groups in either overall survival or cause-specific survival rates at 5 years: 44.2% and 49.0% in the TD resection group, and 39.8% and 47.2% in the TD preservation group, respectively. Furthermore, the number of retrieved mediastinal lymph nodes was significantly greater in the TD resection group than in the TD preservation group (26 vs. 15, p 0.0001). In contrast, TD resection was associated with metastasis to a significantly greater number of distant organs than TD preservation (49 vs. 32, p = 0.049).TD resection did not contribute to improved survival in patients with ESCC but did lead to metastases in more organs than TD preservation. Consequently, indiscriminate TD resection might be avoided in patients with ESCC treated with NACRT followed by esophagectomy.

Neoadjuvant therapy followed by surgery is the standard treatment for locally advanced esophageal cancers. During neoadjuvant therapy, tumor-induced esophageal stenosis or adverse events often cause weight loss. However, little is known about the effects of weight loss during neoadjuvant therapy on postoperative complications or prognosis. We investigated the association between weight loss during neoadjuvant chemotherapy, postoperative infectious complications, and prognosis.Data from OGSG1003, a randomized phase-II trial comparing two regimens of neoadjuvant chemotherapy, cisplatin and fluorouracil plus Adriamycin and cisplatin and fluorouracil plus docetaxel, for locally advanced esophageal squamous cell carcinoma were used. Body weight was measured before neoadjuvant chemotherapy and esophagectomy. Multivariate analysis for infectious complications and prognosis was performed.The study included 134 patients. The median weight loss during neoadjuvant chemotherapy was 2.83% (-2.07% to 6.29%). Postoperative infectious complications were observed in 37 patients who had a significantly higher weight loss during neoadjuvant chemotherapy (5.18% vs. 1.90%, P = 0.002). Multivariate analysis revealed that 5% of weight loss during neoadjuvant chemotherapy was the only independent factor associated with postoperative infectious complications (odds ratio 2.69, 95% confidence interval 1.12-6.46, P = 0.027). Weight loss during neoadjuvant chemotherapy was significantly associated with worse recurrence-free survival in the univariate analysis (log-rank test, P = 0.002), but this association was marginal in the multivariate analysis (hazard ratio 1.73, 95% confidence interval 0.98-3.08, P = 0.058).Severe weight loss during neoadjuvant chemotherapy was an independent risk factor for postoperative infectious complications. Weight maintenance during neoadjuvant chemotherapy may reduce the incidence of postoperative infectious complications.

Fibroblast activation protein (FAP) is known to have prognostic significance in colorectal cancer (CRC). However, FAP and tertiary lymphoid structures (TLSs) have not been associated with each other in predicting the prognosis of CRC recurrence.FAP expression was evaluated by real-time reverse transcription polymerase chain reaction in 195 CRC patients at Osaka International Cancer Institute (first data set). Immunohistochemistry (IHC) was then performed to stain FAP at the invasive margin (IM) and in the central tumour (CT) in 159 CRC patients at Osaka University Hospital (second data set). Consecutive slides were used to evaluate the presence of TLSs in 159 CRC patients from Osaka University Hospital.The high FAP mRNA expression group (n=82) was associated with poor recurrence-free survival (RFS) compared with the low FAP expression group (n=83) (p=0.004). In the second data set, patients with high FAP expression in CT and TLS absence (n=49) showed significantly poorer RFS compared with those with low expression of FAP in CT and presence of TLSs (n=101) (p=0.002).FAP in the CT combined with TLSs was shown to have significant prognostic value in predicting CRC recurrence after curative resection.

We herein investigated the association between early tumor shrinkage (ETS) and depth of response (DpR) and clinical outcomes in patients with metastatic esophageal cancer treated with 2-weekly docetaxel combined with cisplatin plus fluorouracil (bDCF) using data from the JCOG0807, a phase I/II trial of bDCF as first-line chemotherapy for metastatic esophageal cancer.ETS was defined as a percent decrease in the sum of the target lesions' longest diameter after 8 weeks, whereas DpR was defined as a percentage of the maximal tumor shrinkage during the treatment course. Multivariable analyses were conducted to identify significant prognostic variables in progression-free survival (PFS) and overall survival (OS): one for ETS and covariates, and another for DpR and covariates.Among 53 patients, 35 patients with ETS ≥ 20% (66.0%) had longer PFS (7.5 vs. 3.4 months, hazard ratio [HR]: 0.26, 95% confidence interval [95% CI] 0.14-0.49), OS (13.8 vs. 6.1 months, HR 0.20, 95% CI 0.11-0.39), and PPS (6.4 vs. 2.8 months, HR 0.38, 95% CI 0.20-0.72) than those with ETS 20%. In addition, 37 patients with DpR ≥ 30% (69.8%) had longer PFS (7.5 vs. 2.9 months, HR 0.17, 95% CI 0.08-0.34), OS (13.8 vs. 6.0 months, HR 0.14, 95% CI 0.07-0.27), and PPS (6.8 vs. 2.8 months, HR 0.30, 95% CI 0.15-0.58) than those with DpR 30%. Multivariable analyses revealed that each ETS and DpR was an independent factor of longer PFS and OS.ETS and DpR might be associated with clinical outcomes in patients with metastatic esophageal cancer treated with bDCF.

Pancreatic ductal adenocarcinoma (PDAC) contacting major arteries such as the celiac, common hepatic, and superior mesenteric artery is linked to poor prognosis and classified as borderline resectable. Although PDAC involving the gastroduodenal artery (GDA) is considered resectable, the prognostic impact of GDA involvement remains unclear. Here we investigated the prognostic impact of GDA involvement in PDAC after resection.This study included 105 patients with resectable PDAC or borderline resectable with portal vein involvement. Patients were divided into two groups: those with tumor-GDA contact ≤ 180° and those with GDA contact180°. We evaluated the prognostic impact of GDA involvement between these groups.Both recurrence-free and overall survival after the surgery were significantly poorer with GDA contact180° than ≤ 180°. The poorer prognosis with GDA contact180° was verified by multivariate analysis and propensity score matching analysis to match patient backgrounds between the groups. The frequency of postoperative distant metastasis was also significantly higher in patients with GDA contact180°.GDA involvement is an independent factor significantly associated with postoperative survival in PDAC, and the poorer prognosis with GDA involvement may be linked to the development of postoperative distant metastasis.

Background Bursectomy, the total resection of the bursa omentalis, is a standard procedure in gastrectomy for resectable gastric cancer. A phase III trial (JCOG1001) comparing bursectomy and omentectomy alone was terminated early at the interim analysis. The final results of the updated analysis after a minimum follow-up of 5 years are reported here. Methods Patients with histologically proven adenocarcinoma of the stomach (cT3–T4a) were randomized (1 : 1) during surgery to bursectomy or omentectomy-alone groups and then underwent D2 gastrectomy. The primary endpoint was overall survival, analysed on an intention-to-treat basis. Results A total of 1204 patients (602 bursectomy and 602 omentectomy alone) were enrolled between June 2010 and March 2015. The bursectomy group had a significantly higher incidence of Clavien–Dindo grade III–IV intra-abdominal abscess than the omentectomy-alone group (5.5 versus 2.5 per cent respectively; P = 0.008). The updated 5-year overall survival rates were 74.9 (95 per cent c.i. 71.2 to 78.2) per cent in the bursectomy group and 76.5 (72.8 to 79.7) per cent in the omentectomy-alone group; the adjusted HR for death in the bursectomy group was 1.03 (95 per cent c.i. 0.83 to 1.27) (1-sided P = 0.598). Bursectomy did not decrease peritoneal recurrence (12.1 versus 12.3 per cent respectively; P = 1.000). In a multivariable analysis, old age (above 65 years), tumour located in the lower third or posterior wall of the stomach, macroscopic type 3/5, total gastrectomy, and cT4a were independent predictors of poor overall survival, but omentectomy alone was not. Conclusion In D2 gastrectomy, bursectomy is not recommended as a standard procedure for cT3–T4a gastric cancer. Registration number: UMIN000003688 (https://www.umin.ac.jp/ctr/).

Preoperative risk assessment is important in older patients because they often have comorbidities and impaired organ function. We performed preoperative comprehensive geriatric assessment (CGA) for older patients with esophageal cancer.A total of 217 patients over 75 years old who underwent esophagectomy for thoracic esophageal cancer were analyzed. The CGA was performed preoperatively and included the Mini-Mental State Examination (MMSE), Geriatric Depression Score (GDS), vitality index, Barthel index, and instrumental activities of daily living (IADL). We defined the robust group as patients with normal function on every instrument, and the pre-frail and frail groups as those with functional impairment on one instrument or two or more instruments, respectively. We assessed how the CGA correlated with postoperative complications and prognosis.Of the 217 patients, 86 (39.6%) were in the robust group, 68 (31.3%) in the pre-frail group, and 63 (29.0%) in the frail group. Postoperative pneumonia (P = 0.026) and anastomotic leakage (P = 0.032) were significantly more common in the frail group. The frail group had a significantly longer postoperative hospitalization period (P = 0.016) and significantly lower rate of discharge to home (P = 0.016). Overall survival (OS) was significantly worse in the frail group (5-year overall survival rate, frail group versus others, 37.8% versus 52.0%, P = 0.046), but it was not significant on multivariate analysis.The preoperative CGA in older patients with esophageal cancer was associated with risk of postoperative complications.

Total gastrectomy with jejunum or colon reconstruction after esophagectomy is commonly performed in patients with esophageal cancer who have a history of distal gastrectomy. In this study, we examined the safety and effectiveness of double-tract reconstruction (DTR) with preservation of the remnant stomach for said patient population.Twenty-seven esophageal cancer patients with a history of distal gastrectomy who underwent transthoracic esophagectomy between 2010 and 2020 in our institution were retrospectively analyzed; 15 of these patients underwent DTR, whereas 12 underwent completion gastrectomy with jejunal Roux-en-Y reconstruction (RYR). Short-term outcomes, postoperative nutritional indexes, and ghrelin levels were evaluated. Moreover, abdominal lymph-node metastasis and recurrence, which were removed by total residual gastrectomy, were examined to determine the oncological validity of residual stomach preservation.There was no metastasis and recurrence in abdominal lymph nodes, such as #4sa or #11d, which were removed by total residual gastrectomy. Total operation time did not differ between the groups (P = 0.4247). The blood loss for the DTR group was 495 ± 446 mL, whereas that for the RYR group was 844 ± 575 mL (P = 0.0168). Clavien-Dindo grade III or higher complications were not significantly different between the groups (P = 0.7063). The rates of serum total protein values at 6 months in the DTR and RYR groups were 112% ± 12.2% and 102.6% ± 10.7% (P = 0.0403), respectively. The prognostic nutritional indexes at 6 months in the DTR and RYR groups were 108.6% ± 14.5% and 83.2% ± 42.6% (P = 0.0376), respectively.DTR in esophagectomy is safe and effective for patients with a history of distal gastrectomy.

With the global epidemic of SARS-CoV-2, there has been a growing concern regarding the risk of aerosol exposure to healthcare workers and patients during medical/surgical interventions. The Schlieren device is capable of visualizing fine gas-flows by using refractive index differences in the medium. We aimed to reveal the existence of gas leakage from gastro-intestinal endoscopy system by utilizing Schlieren device and to clarify the factors which relates to the amount of gas leakage.The experiments were performed on the excised swine stomach while maintaining a constant pressure environment in the stomach. The System Schlieren (SS100,KatoKoken) was used to visualize possible gas leakages from forceps plugs of endoscopy. We attempted to semi-quantify the leakage by referring to the image of the gas from the forceps plug and by measuring the initial velocity and diffusion area of the leakage.Regardless of the type of forceps plugs, a certain amount of leakage was detected during both insertion and removal of forceps. The initial velocity and the diffusion area of the leakage increased with the increase in intragastric pressure. Semi-quantitative comparison showed that there was a difference in the amount of gas leakage among various forceps plugs. Furthermore, the amount of gas leakage was significantly greater in the forceps plugs that were used repeatedly.It was possible to visualize gas leakages from the gastrointestinal endoscope system using the Schlieren optical device. Avoiding too high intragastric pressure and not using deteriorated plugs may reduce the risk of aerosol exposure.

Alternative splicing plays a vital role in cancer development and progression. The splicing C complex is involved in alternative splicing. However, the role of PRKR-interacting protein 1 (PRKRIP1), a component of the splicing C complex, in colorectal cancer (CRC) remains unclear. This study aimed to determine the clinicopathological, biological and prognostic significance of PRKRIP1 expression in CRC.We used a bioinformatics approach to screen for oncogenes using The Cancer Genome Atlas (TCGA) and Cancer Cell Line Encyclopedia (CCLE) datasets and identified PRKRIP1 as a driver gene on chromosome 7q. The mRNA expression of PRKRIP1 was measured using reverse transcription-quantitative PCR in 165 surgically resected CRC samples in our hospital, and its localization was determined using immunohistochemical staining. Gene Set Enrichment Analysis (GSEA) was performed using TCGA dataset.High PRKRIP1 expression was significantly associated with poor prognosis in both the samples and TCGA dataset. A positive correlation was observed between copy number variation and PRKRIP1 expression in TCGA and CCLE datasets, and the frequency of PRKRIP1 mutations was less than 5%. Immunohistochemistry revealed that PRKRIP1 was located in the cytoplasm of tumor cells. GSEA revealed that PRKRIP1 expression was correlated with apoptosis-related gene sets.PRKRIP1 overexpression may be a poor prognostic biomarker for CRC. Although it is known that PRKRIP1, a spliceosome factor, is essential for splicing, we now revealed the way by which its expression accelerates CRC progression.

Background Serum microRNAs (miRNAs) have been recognized as potential stable biomarkers for various types of cancer. Considering the clinical applications, there are certain critical requirements, such as minimizing the number of miRNAs, reproducibility in a longitudinal clinical course, and superiority to conventional tumor markers, such as carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9. This study aimed to identify serum miRNAs that indicate the recurrence of colorectal cancer (CRC), surpassing inter-tumor heterogeneity. Methods We conducted an analysis of 434 serum samples from 91 patients with CRC and 71 healthy subjects. miRNAs were obtained from Toray Co., Ltd, and miRNA profiles were analyzed using a three-step approach. miRNAs that were highly expressed in patients with CRC than in the healthy controls in the screening phase, and those that were highly expressed in the preoperative samples than in the 1-month postoperative samples in the discovery phase, were extracted. In the validation phase, the extracted miRNAs were evaluated in 323 perioperative samples, in chronological order. Results A total of 12 miRNAs (miR-25-3p, miR-451a, miR-1246, miR-1268b, miR-2392, miR-4480, miR-4648, miR-4732-5p, miR-4736, miR-6131, miR-6776-5p, and miR-6851-5p) were significantly concordant with the clinical findings of tumor recurrence, however their ability to function as biomarkers was comparable with CEA. In contrast, the combination of miR-1246, miR-1268b, and miR-4648 demonstrated a higher area under the curve (AUC) than CEA. These three miRNAs were upregulated in primary CRC tissues. Conclusion We identified ideal combinatorial miRNAs to predict CRC recurrence.

Two prominent patient positions during thoracoscopic esophagectomy are the left lateral decubitus position (LP) and the prone position (PP). However, whether the patient position during thoracoscopic esophagectomy influences short-term outcomes, especially postoperative pneumonia, remains unclear. We aimed to elucidate the impact of patient position on the occurrence of postoperative pneumonia.We analyzed 9850 patients who underwent oncologic thoracoscopic esophagectomies between 2016 and 2019 from the National Clinical Database. We compared the short-term outcomes between the LP and PP groups, and the primary outcome measure was the incidence of postoperative pneumonia.This study included 2637 (26.8%) and 7213 (73.2%) patients in the LP and the PP groups, respectively. The baseline characteristics of the two groups were well-balanced. Compared with the LP group, the PP group had a longer operative time and less blood loss. There were no significant differences in the incidences of postoperative pneumonia, recurrent laryngeal nerve palsy, anastomotic leakage, severe complications, and reoperation between the groups. Meanwhile, prolonged ventilation and surgery-related mortality occurred more frequently in the LP than in the PP group (P 0.001 and 0.046, respectively). After multivariable adjustment, the patient position did not significantly influence the incidence of postoperative pneumonia (odds ratio 0.91, 95% confidence interval 0.80-1.04).Although prolonged ventilation and surgery-related mortality occurred more frequently in the LP group than in the PP group, the patient position did not significantly influence the occurrence of postoperative pneumonia.

Due to the overwhelming spread of SARS-CoV-2 and its disruption of the healthcare system, delays and reduced numbers were reported for colorectal cancer screening, colonoscopies, and surgery during the COVID-19 pandemic. This multicenter retrospective study investigated the still poorly understood impact of the COVID-19 pandemic on colorectal cancer treatment in Japan.This study was organized by the Clinical Study Group of Osaka University, which comprised 32 major institutions in Osaka. We retrospectively analyzed the number of surgeries and colonoscopies performed and the characteristics of patients who underwent surgery for colorectal cancer between March 2019 and February 2021. We compared data collected before and during the COVID-19 pandemic. We also assessed the methods used for detecting colorectal cancer, including fecal occult blood test, abdominal symptoms, and anemia.The COVID-19 pandemic caused reductions in the annual numbers of surgeries (3569 vs 3198) and colonoscopies (67 622 vs 58 183) performed in the 2020 fiscal year, compared to the 2019 fiscal year. During the COVID-19 pandemic, a significantly lower proportion of patients were treated for clinical stages ≤I (24.2% vs 26.9%;The COVID-19 pandemic reduced the number of colonoscopies and surgeries performed for colorectal cancer and hindered the detection of asymptomatic early-stage cancers, and its impact varied by hospital size.

The very-low-voltage (VLV) mode in electrosurgery can stably and deeply energize tissues even if the local electrical resistance changes with energization. Therefore, in electrosurgical hemostasis, the VLV mode is more reliable than other coagulation modes. In clinical practice, the appropriate use of combined saline drip and blood suction under the VLV mode can further enhance coagulation ability. However, the detailed mechanism is not known. The current study aimed to evaluate the association between electrosurgical activation time (ET) and hemostatic tissue effect (HTE) under the VLV mode. Further, the effect of saline drip and suction on power consumption and HTE was validated.Twelve female pigs weighing 35 kg were included in the experiment. A liver hemorrhage model was established via an open abdominal procedure, and hemostasis in the hemorrhagic lesion was attempted using the VLV mode under different conditions (ET: 3, 6, 9, and 12 s, with/without saline drip and/or continuous suction). Electrical data (such as voltage, current, and resistance) during coagulation were extracted. Then, the vertical/horizontal extent of HTE was assessed, and the hemostasis outcome (successful or failed) was recorded.The vertical/horizontal HTE, power consumption, and integrated current value were positively correlated with the ET. The coagulation depth deepened with saline drip (p 0.01). However, it was not affected by continuous suction (p = 0.20). The HTE area increased with saline drip (p 0.01) and decreased with suction (p 0.01). The power consumption and integrated current increased with saline drip (p 0.01) and decreased with suction (p 0.01). The success rate of hemostasis decreased with saline drip alone (31of 48 trials [success rate = 64.5%] in the saline drip group and 44/48 trials (success rate = 91.7%) in the control group). However, it improved with continuous suction (46/48 trials [success rate = 95.8%]).The electrosurgical activation time was positively correlated with hemostatic tissue effect. Saline drip increased heat transfer efficiency but decreased the success rate of hemostasis. Therefore, the use of continuous suction in addition to saline drip increased hemostatic efficiency.

Colorectal cancer (CRC) is a major cause of cancer-related deaths. Metastasis is enhanced through epithelial-mesenchymal transition (EMT), a process primarily induced by the transforming growth factor beta (TGF-β)-mediated canonical Smad pathway. This study focused on plexin D1 (PLXND1), a chemoreceptor for the ligand SEMA3E to mechanosensory, showing that PLXND1 induces EMT via activation of the PI3K/AKT pathway in CRC cells. The findings showed that PLXND1-knockdown decreases cell migration and invasion significantly, and that the binding of p61-SEMA3E to the PLXND1 enhances the invasiveness and migration through EMT. Furin inhibitor suppresses EMT, decreasing cell migration and invasion. Furin cleaves full-length SEMA3E and converts it to p61-SEMA3E, suggesting that furin inhibitors block PLXND1 and p61-SEMA3E binding. Furin is a potential therapeutic target for the purpose of suppressing EMT by inhibiting the binding of p61-SEMA3E to PLXND1. In vivo experiments have shown that PLXND1-knockdown suppresses EMT. Mesenchymal cells labeled with ZEB1 showed heterogeneity depending on PLXND1 expression status. The high-expression group of PLXND1 in 182 CRC samples was significantly associated with poor overall survival compared with the low-expression group (P = 0.0352, median follow-up period of 60.7 months) using quantitative real-time polymerase chain reaction analysis. Further research is needed to determine whether cell fractions with a different expression of PLXND1 have different functions.

One upside of cervical esophageal carcinoma is that radical surgery can be performed by laryngectomy, even for tumors with tracheal invasion. However, this approach drastically reduces the quality of life, such as by losing the vocal function. Cervical esophageal carcinoma is rare, and no comprehensive reports have described the current state of surgery. Using a Japanese nationwide web-based database, we analyzed the surgical outcomes of cervical esophageal carcinoma to evaluate the impact of larynx-preserving surgery.Based on the Japan National Clinical Database, 215 surgically treated cases of cervical esophageal carcinoma between January 1, 2018, and December 31, 2019, were enrolled. Clinical outcomes were compared between the larynx-preserved group and the laryngectomy group.Ninety-four (43.7%) patients underwent larynx-preserving surgery. A total of 177 (82.3%) patients underwent free jejunum reconstruction. More T4b patients and more patients who underwent preoperative radiotherapy were in the laryngectomy group. There were no significant differences in the frequency and the severity of morbidities between the two groups. However, in the laryngectomy group, in-hospital death within 30 days after surgery was observed in 1 patient, and the postoperative hospital stay was significantly longer (P = 0.030). In the larynx-preserved group, recurrent nerve paralysis was observed in 24.5%. Re-operation (35.3%, P = 0.016), re-intubation (17.6%, P = 0.019) and tracheal necrosis (17.6%, P = 0.028) were significantly more frequent in patients who underwent pharyngolaryngectomy with total esophagectomy and gastric tube reconstruction than in others.Larynx-preserving surgery was therefore considered to be feasible because it was equivalent to laryngectomy regarding the short-term surgical outcomes.

The cornerstone of treating colorectal cancer (CRC) is generally a surgical resection with lymph node (LN) dissection. The tools for predicting lymph node metastasis (LNM) in submucosal (SM) CRC are useful to avoid unnecessary surgical resection.Retrospectively, we analyzed 526 consecutive patients with SM CRC who underwent surgical resection at the Osaka International Cancer Institute, Osaka University Hospital, and Minoh City Hospital, Japan, between 1984 and 2012. The Osaka International Cancer Institute group and the Osaka University Hospital group were randomly divided into a training set and a test set of 2:1. The prediction model was validated in Minoh City Hospital.We partitioned patients using three risk factors involved in the presence or absence of LNM in SM CRC: lymphatic invasion (Ly), budding grade (BD) and the depth of submucosal invasion (DSI) (cut-off value 2789 μm) that were significantly different in the multivariate analysis. As a result, a predictive model of "LNM5%" when "Ly negative and DSI2789 μm" was evaluated. We similarly partitioned by DSI 3000 μm as easy-to-evaluate values in clinical use. We developed the additional model for predicting LNM is 1.05%, that is, LNM5%, when there are "Ly negative and DSI3000 μm."As a limitation, only patients who underwent surgical resection were included in this study. This predictive model could help clinicians and CRC patients decide on the additional surgery required after endoscopic resection.

Surgery for esophageal cancer (EC) causes morphological and functional changes in the upper gastrointestinal tract, resulting in postoperative weight loss (PWL). PWL has been shown to lead to poor nutritional status and immunocompetence, which may worsen the prognosis for several types of cancer. However, few reports have examined the relationship between weight loss (WL) in the early postoperative period and cancer prognosis.A total of 421 esophageal cancer patients underwent curative esophagectomy at Osaka University Hospital from 2010 to 2016. Based on the patients' body weight 1.5 months after surgery, they were classified into severe WL (n = 50) and slight-moderate WL (n = 371) groups.The 5-year overall survival (OS), cancer-specific survival (CSS), and recurrence-free survival (RFS) were significantly lower in the severe WL group than the slight-moderate WL group (p = 0.0002, p 0.0001, and p = 0.0004, respectively). In the multivariate analysis, tumor invasion depth (pT3, 4), lymph node metastasis (pN2, 3), preoperative Prognostic Nutrition Index ( 45), postoperative complications (≥ G3), and severe WL were independent prognostic factors for CSS (hazard ratio [HR] 2.5, 95% confidence interval [CI] 1.7-3.7; HR 1.6, 95% CI 1.1-2.4; HR 1.9, 95% CI 1.3-2.8; HR 1.6, 95% CI 1.1-2.4; and HR 2.7, 95% CI 1.7-4.2, respectively). In a multivariate analysis of risk factors leading to severe WL, thoracotomy (VATS) and postoperative MAX CRP (high) were independent risk factors (odds ratio [OR 0.48, 95% CI 0.24-0.97; OR 1.9, 95% CI 1.0-3.5).Early PWL would be a useful marker of poor cancer prognosis in EC patients. Highly inflammatory conditions due to surgical invasion and postoperative complications may contribute to early PWL.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment. Since clinical benefits are limited to a subset of patients, we aimed to identify peripheral blood biomarkers that predict the efficacy of the anti-programmed cell death protein 1 (PD-1) antibody (nivolumab) in patients with gastric cancer.We collected peripheral blood samples from gastric cancer patients (n = 29) before and after treatment with nivolumab and investigated the relationship between the frequency of surface or intracellular markers among nivolumab-binding PD-1Patients with a high frequency of CD103 among PD-1A high frequency of CD103 among PD-1

A synthetic peptide 'TDM-623' is a promising hemostatic material for endoscopic surgery in the gastrointestinal tract. However, its stability under gastric/pancreatic secretion has yet to be shown. Hence, this study verified the stability of TDM-623 under digestive enzyme.TDM-623 (1 mL) was applied to a dish and left at 37 °C for gel formation. Artificial gastric/pancreatic juice and saline were applied to each dish (The amount of dissolved peptides originating from the TDM-623 gel after gastric juice exposure was negligible compared to its original amount: a maximum of 10.3% dissolved after 48 h. No significant amounts of dissolved peptides were seen at any timepoint of exposure to pancreatic juice. Also, there were neither morphological nor physical changes after exposure to digestive enzymes for 48 h.This study suggests that TDM-623 is sufficiently stable under digestive enzyme. TDM-623 is thus expected to be a durable hemostatic material that protect wound left by endoscopic surgery.

To assess pain management in patients post-sacrectomy, focusing on opioid use, and to identify the factors associated with postoperative pain.Patients who underwent resection of locally recurrent rectal cancer (LRRC) with concomitant sacrectomy at one of two hospitals between 2007 and 2020 were reviewed retrospectively. We examined the use of opioids preoperatively and postoperatively. Patients were classified into high and low sacrectomy groups based on the sacral bone resection level passing through the S3 vertebra.Sixty-four patients were enrolled. Opioid use was significantly higher in the high sacrectomy group than in the low sacrectomy group at all times assessed: on postoperative days 7, 14, 30, 90, 180, and 365. Opioid use 3 months after locally recurrent rectal cancer surgery was significantly higher in patients with local re-recurrence of the tumor than in those without re-recurrence (p 0.05), and the median morphine-equivalent opioid use 3 months postoperatively was significantly higher in the high sacrectomy group (30 vs. 0 mg/day; p 0.05).Opioid use after concomitant sacrectomy for LRRC was higher in the high sacrectomy group. Prolonged postoperative pain or increasing pain was associated with local recurrence.

Background: Defecation status is an important determinant of quality of life. Previous studies showed that postoperative defecation disorders occurred after open surgery for ulcerative colitis (UC)...

Background The treatment efficacy of immune checkpoint inhibitors (ICIs) is limited, and biomarkers that identify responders are urgently needed. We investigated whether C-reactive protein (CRP) kinetics are associated with the treatment efficacy of ICIs and prognosis in upper gastrointestinal cancers. Methods We analysed 76 gastric cancer patients treated with nivolumab monotherapy. Patients were classified as CRP-spike, CRP-flat, or CRP-increase according to CRP kinetics within 6 weeks after nivolumab initiation, and the treatment response and prognosis were compared. We further validated this classification in 71 oesophageal cancer patients with nivolumab monotherapy. Results In the gastric cancer cohort, the CRP-spike, CRP-flat, and CRP-increase subgroups included 9, 37, and 30 patients, respectively. The CRP-spike subgroup had higher disease control rates than the CRP-increase subgroup (p = 0.0068) and had significantly better progression-free survival (PFS) (vs. CRP-flat: p = 0.045, CRP-increase: p = 0.0001). Multivariate analysis for PFS identified CRP-spike (HR = 0.38, p = 0.029) as an independent favourable prognostic factor. In the oesophageal cancer cohort, the CRP-spike, CRP-flat, and CRP-increase subgroups included 13, 27, and 31 patients, respectively, and multivariate analysis for PFS also identified CRP-spike (HR = 0.28, p = 0.0044) as an independent favourable prognostic factor. Conclusions CRP kinetics may be useful in predicting the long-term outcome of nivolumab treatment in upper gastrointestinal cancers.

The incidence of inflammatory bowel disease (IBD) is increasing worldwide. It is reported that TGF-β/Smad signal pathway is inactivated in patients with Crohn’s disease by overexpression of Smad 7. With expectation of multiple molecular targeting by microRNAs (miRNAs), we currently attempted to identify certain miRNAs that activate TGF-β/Smad signal pathway and aimed to prove in vivo therapeutic efficacy in mouse model. Through Smad binding element (SBE) reporter assays, we focused on miR-497a-5p. This miRNA is common between mouse and human species and enhanced the activity of TGF-β/Smad signal pathway, decreased Smad 7 and/or increased phosphorylated Smad 3 expression in non-tumor cell line HEK293, colorectal cancer cell line HCT116 and mouse macrophage J774a.1 cells. MiR-497a-5p also suppressed the production of inflammatory cytokines TNF-α, IL-12p40, a subunit of IL-23, and IL-6 when J774a.1 cells were stimulated by lipopolysaccharides (LPS). In a long-term therapeutic model for mouse dextran sodium sulfate (DSS)-induced colitis, systemic delivery of miR-497a-5p load on super carbonate apatite (sCA) nanoparticle as a vehicle restored epithelial structure of the colonic mucosa and suppressed bowel inflammation compared with negative control miRNA treatment. Our data suggest that sCA-miR-497a-5p may potentially have a therapeutic ability against IBD although further investigation is essential.

Background Driver alterations may represent novel candidates for driver gene-guided therapy; however, intrahepatic cholangiocarcinoma (ICC) with multiple genomic aberrations makes them intractable. Therefore, the pathogenesis and metabolic changes of ICC need to be understood to develop new treatment strategies. We aimed to unravel the evolution of ICC and identify ICC-specific metabolic characteristics to investigate the metabolic pathway associated with ICC development using multiregional sampling to encompass the intra- and inter-tumoral heterogeneity. Methods We performed the genomic, transcriptomic, proteomic and metabolomic analysis of 39–77 ICC tumour samples and eleven normal samples. Further, we analysed their cell proliferation and viability. Results We demonstrated that intra-tumoral heterogeneity of ICCs with distinct driver genes per case exhibited neutral evolution, regardless of their tumour stage. Upregulation of BCAT1 and BCAT2 indicated the involvement of ‘Val Leu Ile degradation pathway’. ICCs exhibit the accumulation of ubiquitous metabolites, such as branched-chain amino acids including valine, leucine, and isoleucine, to negatively affect cancer prognosis. We revealed that this metabolic pathway was almost ubiquitously altered in all cases with genomic diversity and might play important roles in tumour progression and overall survival. Conclusions We propose a novel ICC onco-metabolic pathway that could enable the development of new therapeutic interventions.

Background Exon 18 D842V, which is a point mutation from aspartic acid to valine at codon 842, is the most frequent mutation in Platelet-Derived Growth Factor Receptor alpha (PDGFRA)-mutated gastrointestinal stromal tumor (GIST). In the Japanese GIST guidelines, no standard systematic therapy is available for this type of GIST, which is refractory after recurrence. Recently, pimitespib (PIMI), a novel heat shock protein 90 (HSP90) inhibitor, was approved for the treatment of advanced GIST in a phase III study. This report presents a case of a long-term response to PIMI in GIST with PDGFRA D842V mutation. Case presentation A 55-year-old woman was diagnosed with primary GIST of the stomach and underwent partial gastrectomy. Eight years after the operation, recurrent GISTs were identified as multiple recurrent peritoneal GISTs in the upper right abdomen and pelvic cavity. We administered tyrosine kinase inhibitors, but they achieved poor effects. After failure of the standard treatment, PIMI was administered and achieved a partial response in the patient. The highest reduction rate was 32.7%. After PIMI failed, we performed multiplex gene panel testing, which revealed the PDGFRA D842V mutation. Conclusions We report the first case of long-term response to PIMI in PDGFRA D842V mutant GIST. Pimitespib may be effective for treating GIST harboring this mutation by inhibiting HSP90.

Background: To assess the potential clinical utility of cell-free DNA (cfDNA)-based biomarkers for identifying gastric cancer (GC) patients who benefit from nivolumab. Methods: From 31 GC patients treated with nivolumab monotherapy (240mg/body, Bi-weekly) in 3rd or later line setting, we prospectively collected blood samples at baseline and before the 3rd dose. We compared cfDNA-based molecular findings, including microsatellite instability (MSI) status, to tissue-based biomarkers. We assessed the clinical value of blood tumor mutation burden (bTMB) and copy number alterations (CNA) as well as the cfDNA dynamics. Results: The concordance between deficient-MMR and cfDNA-based MSI-high was 100% (3/3). Patients with bTMB≥6 mut/Mb had significantly better progression-free survival (PFS) and overall survival (OS); however, such significance disappeared when excluding MSI-High cases. The combination of bTMB and CNA positivity identified patients with survival benefit regardless of MSI status (both PFS and OS, P≥6mut/Mb and CNAnegative. Moreover, patients with decreased bTMB during treatment had a better disease control rate (P=0.04) and longer PFS (P=0.04). Conclusions: Our results suggest that a combination of bTMB and CNA may predict nivolumab efficacy for GC patients regardless of MSI status. bTMB dynamics have a potential utility as an on-treatment biomarker.

Background Tertiary lymphoid structures (TLSs) are ectopic lymphoid aggregates in non-lymphoid tissues, which are associated with improved prognosis in some cancer types. This study aimed to investigate the clinical significance of TLSs in oesophageal cancer (EC). Methods In a series of 316 EC surgical specimens from two different institutes, we evaluated the density and maturity of peritumoral TLSs using haematoxylin/eosin, immunohistochemistry, and multiplex immunofluorescence staining. We analysed the association between TLSs and clinicopathological parameters. The clinical significance of TLSs was further evaluated in a different cohort of 34 patients with recurrent EC treated with anti-PD-1 antibody. Results Tumours with high TLS density predominantly consisted of matured TLSs. High TLS density was significantly associated with less advanced tumour stage, absence of lymphatic/vascular invasion, better serum nutrition parameters (neutrophils count, albumin, neutrophil-to-lymphocyte ratio, and prognostic nutritional index), and prolonged survival. This survival trend was more remarkable in cases with matured TLSs, which represented an increased population of CD138+ plasma cells. In the second EC cohort, TLS density predicted the clinical response to anti-PD-1 antibody and patient survival. Conclusion The density and maturity of peritumoral TLSs are useful parameters for predicting long-term survival and response to anti-PD-1 antibody treatment in EC patients.

Innate lymphoid cells (ILC) are responsible for mucosal tissue homeostasis and are involved in the progression and suppression of several types of cancer. However, the effects of ILCs on colorectal cancer are poorly understood. We characterized human ILCs in normal colon and colorectal cancer tissue, investigating their role in the tumor immune microenvironment. Normal mucosa and tumor tissues were obtained from patients with colorectal cancer, and the cells were isolated by enzymatic digestion. NKp44+ ILC3s with high expression of tertiary lymphoid structure (TLS) formation–related genes, including LTA, LTB, and TNF, accumulated in the normal colonic mucosa and T1/T2 tumors. However, the number of NKp44+ ILC3s was significantly reduced in T3/T4 tumors compared with normal colonic mucosa and T1/T2 tumors. NKp44+ ILC3s present in T3/T4 tumors had decreased expression of TLS formation–related genes, whereas stromal cells had decreased expression of CXCL13, CCL19, and CCL21. The decreasing number of NKp44+ ILC3s during tumor progression correlated with the TLS density in tumors. Thus, our results indicate that NKp44+ ILC3s infiltrate colorectal cancer tissue, but the number of cells decreases in T3/T4 tumors with associated decreases in TLS induction.

Supplementary figures S1-7

Supplementary Table S1 shows patient characteristics.